(a) Field of the Invention
The present invention is directed to an aqueous ophthalmic solution of olopatadine or a pharmaceutically acceptable salt thereof. The solution contains a high concentration of olopatadine and a mixture of at least two non-ionic surfactants for providing enhanced solubility of olopatadine. The invention is further directed to the use of said solution for treating or providing enhanced relief from symptoms of ocular allergic disorders (e.g. conjunctivitis).
(b) Description of the Related Art
Olopatadine hydrochloride is a carboxylic acid derivative of doxepin, chemically described as 11-[(Z)-3(Dimethylamino) propylidene]-6-11dihydrodibenz [b,e] oxepin-2-acetic acid, hydrochloride [C21H23NO3.HCl], as disclosed in U.S. Pat. Nos. 4,871,865 and 4,923,892 both assigned to Burroughs Wellcome. Olopatadine has antihistamine and antiasthmatic activity.
Olopatadine hydrochloride is commercially available in the United States as 0.1% and 0.2% sterile ophthalmic solutions under the brand names Patanol® and Pataday® respectively, both marketed by Alcon. According to its prescribing information, Patanol® is indicated for the treatment of signs and symptoms of allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.1% olopatadine, 0.01% benzalkonium chloride as preservative, dibasic sodium phosphate, sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust the pH) and purified water. The formulation has a pH of about 7, and osmolality of about 300 mOsm/kg. According to its prescribing information, Pataday® is indicated for the treatment of ocular itching associated with allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.2% olopatadine, 0.01% benzalkonium chloride as preservative, povidone, dibasic sodium phosphate, sodium chloride, edetate disodium, hydrochloric acid and/or sodium hydroxide (to adjust the pH) and purified water. The formulation has a pH of about 7, and osmolality of about 300 mOsm/kg.
A high concentration olopatadine product has been approved in the United Stated as 0.7% sterile ophthalmic solution under the brand name Pazeo®, marketed by Alcon. Pazeo® is indicated for the treatment of ocular itching associated with allergic conjunctivitis and the approved ophthalmic solution contains olopatadine hydrochloride equivalent to 0.7% olopatadine. Such a high concentration olopatadine formulation is believed to provide enhanced relief from symptoms of ocular allergic conjunctivitis, particularly late phase symptoms of ocular allergic conjunctivitis. The formulation contains povidone, hydroxypropyl-γ-cyclodextrin, polyethylene glycol 400, hydroxypropyl methylcellulose, boric acid, mannitol, benzalkonium chloride 0.015% (preservative), hydrochloric acid/sodium hydroxide (to adjust pH), and purified water.
Several formulations have been suggested in the art with an objective to prepare stable aqueous solution of olopatadine.
U.S. Pat. No. 6,995,186 discloses a topically administrable solution composition comprising approximately 0.17-0.62 w/v % olopatadine and a polymeric physical stability enhancing ingredient such as polyvinylpyrrolidone or polystyrene sulfonic acid.
U.S. Pat. No. 8,791,154 discloses an ophthalmic solution of olopatadine comprising at least 0.67 w/v % olopatadine and a cyclodextrin derivative along with other ingredients. The '154 patent teaches that the formulations containing a mixture of solubilizing agents such as polyethylene glycol, polyvinyl pyrrolidone, tyloxapol and other solubilizers do not provide long term stable composition of 0.7% w/v olopatadine and such composition begin to precipitate after some time.
PCT Application Pub. No. WO 2008093358 discloses an aqueous topical solution of olopatadine in concentrations ranging from about 0.17% to about 0.65% and further comprising a solubilizer selected from tyloxapol, vitamin E tocopheryl PEG diesters of dicarboxylic acids and mixtures thereof. The application further discloses that various solubilizers including hydroxypropyl-β-cyclodextrin (HP-β-CD), polysorbate 20, polysorbate 80, propylene glycol, hydroxypropyl methylcellulose 2910 (HPMC E4M premium), polyvinyl pyrrolidone K-30, xanthan gum, sodium carboxymethylcellulose (Sodium CMC), carbopol 934P, polyvinyl alcohol, and mixtures thereof are not sufficient to maintain olopatadine in solubilized form in the solution.
Indian Patent Application No: 748/MUM/2006 discloses a stable olopatadine hydrochloride solution containing hydroxypropyl-β-cyclodextrin as the stability enhancing ingredient so as to enhance the physical stability of the solution.
U.S. Patent Application Publication No. 20120022149 discloses ophthalmic compositions containing relatively high concentrations of a solubility enhancing polymer (e.g., polyether polymer such as PEG 4000 to 8000, polyvinyl polymer such as PVP or a combination thereof) for providing enhanced solubility of one or more therapeutic agents, preferably olopatadine.
U.S. Patent Application Publication No. 20110082145 discloses a combination formulation of olopatadine and a PDE4 inhibitor compound, and their use for treating and/or preventing allergic or inflammatory disorders of the eye, ear, skin, and nose. The concentration of olopatadine in the formulation may be at least 0.05% w/v and may contain polyethylene glycol and polyvinyl pyrrolidone as lubricants and/or viscosity agents, respectively.
The obstacle for preparing topical olopatadine aqueous solutions and particularly for high concentration olopatadine is the stability of the aqueous solutions over the shelf storage period. Olopatadine aqueous solutions of concentrations of 0.17% or higher were found to have physical stability problems during storage over the shelf life of the product. The olopatadine precipitates or crystallizes out of the formulated solution at concentrations higher than 0.17%. Solubilizing further high concentrations of olopatadine such as more than 0.67% w/v in a stable manner has proven even more difficult since olopatadine, by itself, is only soluble in water (pH about 7.0) at room temperature up to a concentration of about 0.18 w/v %.
Known solvents and polymers such as polyethylene glycol (PEG) 400 and polyvinyl pyrrolidone (PVP), when used at reasonably desirable concentrations, have proven incapable, alone or in combination, of solubilizing sufficient concentrations of olopatadine in compositions having approximately neutral pH. Further, it is also known that other solvents such as higher molecular weight PEGs such as PEG 6000 can significantly enhance solubility of olopatadine. However, such PEGs cause risk of discomfort when administered to humans.
Thus there is a need to create a desirable olopatadine formulation that not only solubilizes sufficient amounts of olopatadine, but also allows the formulation to achieve other desirable pharmaceutical characteristics. The present invention is directed at an ophthalmic composition that can provide high concentrations of olopatadine topically to the eye. Further, the present invention is directed to such a composition wherein the olopatadine is solubilized in solution in a stable manner.